The present invention relates to a process for preparing the derivatives of an inhibitor of Angiotension Converting Enzyme (hereinafter referred to as "ACE"). More particularly, it relates to a process for preparing N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine derivatives.
Life expectancy of a person is prolonged by the breakthrough of medical technology, this contribution yields aged people. Most of the elders suffer from hypertension in some degree. Reducing blood pressure medicine is in mass demand for curing of hypertension. Developing a simple and convenient method to produce a compound that inhibits the ACE activity by means of lowering blood pressure drug thereof is long for decades.
According to U.S. Pat. No. 4,374,829 discloses that by using the derivative of L-alanine-L-proline dipeptide as the reacting agent connects other groups on the N-terminus. During the reaction, a Schiff's base obtained first then undergoes hydrogenation. Meanwhile a mixture of diastereoisomers is RSS and SSS. Among these two isomers, only SSS configuration compound can be used for clinical purpose. Therefore followed by the method mentioned above to separate the SSS configuration from the mixture is the final and critical step as a complete process.
Maintaining the assured stereo chemical structure and avoiding from different one can diminish the difficulties in purification process. In European Patent EP 0215335 discloses that the C-terminus of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine (hereinafter referred as to NEPA therein reacted with phosgene to form N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride. Followed by the addition reaction with organic or inorganic slats of L-proline to form derivative of dipeptide. The result yields N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline, a prodrug of ACE inhibitory with SSS configuration of the Enalapilat (common name is Enalapril (2)). ##STR2## Although the selectivity of dimensional structure and recovery rate thereof is relatively high during the reaction, it is needed for toxic phosgene in process. As for the purpose of industrial production, there should be a special design for avoiding from the leakage of phosgene, as critical control point for safety control of hazards.
Furthermore, PCT, WO 9602564 discloses that a yield of active thionyldiimidazole by reacting imidazole with thionyl chloride can react with NEPA to form an intermediate of acetyl base; this carboxylate intermediate can again react with amino acid to form an ACE inhibitory compound. In this reaction, using the derivative of sulfite is the derivative of imidazole can cause the second reaction, and moreover the accompanying byproduct will be produced. Therefrom unless purify from the byproduct, this process can not be accounted for a complete process.